Ann Campbell

Safety and Feasibility of Autologous Myoblast Transplantation in Patients With Ischemic Cardiomyopathy Four-Year Follow-Up

Background—Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function. Methods and Results—Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction <40% were enrolled in the CABG arm. In a second arm, 6 patients underwent LVAD implantation as a bridge to heart transplantation, and patients donated their explanted native hearts for testing at the time of heart transplantation. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term, unexpected adverse events. Follow-up positron emission tomography scans showed new areas of glucose uptake within the infarct scar in CABG patients. Echocardiography measured an average change in left ventricular ejection fraction from 28% to 35% at 1 year and of 36% at 2 years. Histological evaluation in 4 of 6 patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. Conclusions—These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.

One-Year Follow-Up of Feasibility and Safety of the First U.S., Randomized, Controlled Study Using 3-Dimensional Guided Catheter-Based Delivery of Autologous Skeletal Myoblasts for Ischemic Cardiomyopathy (CAuSMIC Study)

OBJECTIVES The aim of this study was to test safety and feasibility of myoblast transplantation with the Biosense-NOGA (Diamond Bar, California) 3-dimensional-guided endomyocardial delivery system. BACKGROUND Previous Phase-1 trials showed feasibility of epicardial injection of myoblasts. However, catheter-based delivery has several advantages: it can be applied on high-risk patients, the procedure can be repeated, and it is associated with less morbidity and mortality. METHODS Twenty-three subjects, with previous myocardial infarction and heart failure, New York Heart Association (NYHA) functional class II to IV, were enrolled, 11 control and 12 treatment subjects. To assess safety, physical exam, electrocardiogram, continuous rhythm monitoring, quality of life assessments, and heart function were evaluated at baseline and follow-up until 1 year. RESULTS There was favorable safety: no difference between groups in arrhythmias, and no deaths. Treated subjects showed sustained improvements in NYHA and Minnesota Living with Heart Failure Questionnaire (MLHFQ) compared with control subjects (NYHA, -1.0 point in treatment vs. +0.3 point in control group, p < 0.0004; MLHFQ, -14 point in treatment vs. +1 point in the control group, p = 0.004). Blinded core laboratory echocardiography evaluations showed sustained reductions in the treatment versus control in end diastolic diameter (-0.03 cm vs. +0.05 cm, p = 0.07) and end systolic diameter (-0.05 cm vs. +0.1 cm, p = 0.07). Finally, NOGA voltage mapping demonstrated improved voltage measurements (+1.0 mV, p = 0.008). CONCLUSIONS This trial of myoblast transplantation via catheter into heart failure patients demonstrated safety and feasibility. Treated patients showed improvement in NYHA, MLHFQ, ventricular viability, and evidence of reverse ventricular remodeling. These data demonstrate positive safety outcomes and warrant initiation of larger phase 2, double-blind, placebo-controlled clinical trials.

Feasibility and safety of autologous myoblast transplantation in patients with ischemic cardiomyopathy.

Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device implantation (LVAD). In addition, we sought to gain preliminary information on graft survival and any potential improvement of cardiac function. Eighteen patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twelve patients with a history of previous myocardial infarction (MI) and a left ventricular ejection of less than 30% were enrolled in the CABG arm. In a second arm, six patients underwent LVAD implantation as a bridge to heart transplantation and were required to donate their heart for testing at the time of heart transplant. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term unexpected adverse events. Follow-up PET scans showed new areas of viability within the infarct scar in CABG patients. Echocardiography measured an average improvement in left ventricular ejection fraction (LVEF) from 25% to 34%. Histological evaluation in four out of five patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. These interim results demonstrate survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality may offer a potential therapeutic treatment for end-stage heart disease.

Cell Therapy for Cardiovascular Disease: A Comparison of Methods of Delivery

The field of myocardial regeneration utilizing novel cell-based therapies, gene transfer, and growth factors may prove to play an important role in the future management of ischemic heart disease and cardiomyopathy. Phases I and II clinical trials have been published for a variety of biologics utilizing four methods of delivery: systemic infusion, intracoronary infusion, transvenous coronary sinus, and intramyocardial. This review discusses the advantages and disadvantages of the delivery approaches above.

Endoventricular Transplantation of Allogenic Skeletal Myoblasts in a Porcine Model of Myocardial Infarction

Purpose: To assess the technical feasibility of percutaneous endoventricular injection of skeletal myoblasts into an infarcted porcine myocardium. Methods: A skeletal muscle biopsy was obtained from a donor pig and processed for myoblast expansion in vitro. Myocardial infarction was induced in a host pig via fibrin coil placement in the left anterior descending artery. Four weeks later, electromechanical mapping of the left ventricle identified the infarction site, into which ∼200 million allogenic cells obtained from the muscle biopsy were directly injected (0.1 mL/injection at 25 sites) from inside the ventricular cavity via a needle injection catheter inserted through the femoral artery. Ten days after transplantation, the injected heart was evaluated histologically for the presence of myoblasts. Results: Electrocardiography, echocardiography, left ventricular angiography, and electromechanical mapping confirmed the myocardial infarction. During the cell transfer procedure, premature ventricular contractions confirmed needle placement in the endocardium. Histological evaluation of the host heart 10 days after cell transfer revealed living myoblasts and multinucleated myotubes in the infarcted region, indicating successful transplantation. Conclusions: Direct myoblast transplantation into infarcted porcine myocardium using an endoventricular injection was technically feasible. The results in this model show that transplanted myoblasts were able to survive for 10 days after transplantation.

A randomized, double-blind, placebo-controlled, multicenter, pilot study of the safety and feasibility of catheter-based intramyocardial injection of AdVEGF121 in patients with refractory advanced coronary artery disease

The experience with direct myocardial injection of adenovirus encoding angiogenic growth factor is limited to invasive surgical approach. Accordingly, we sought to evaluate, for the first time, in a randomized, double‐blind, placebo‐controlled, phase I pilot study the safety and feasibility of percutaneous catheter‐based intramyocardial delivery of a replication‐deficient adenovector encoding the 121‐amino‐acid isoform of vascular endothelial growth factor (AdVEGF121).